Document Detail


The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma.
MedLine Citation:
PMID:  23298836     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Fusion genes are chromosomal aberrations that are found in many cancers and can be used as prognostic markers and drug targets in clinical practice. Fusions can lead to production of oncogenic fusion proteins or to enhanced expression of oncogenes. Several recent studies have reported that some fusion genes can escape microRNA regulation via 3'-untranslated region (3'-UTR) deletion. We performed whole transcriptome sequencing to identify fusion genes in glioma and discovered FGFR3-TACC3 fusions in 4 of 48 glioblastoma samples from patients both of mixed European and of Asian descent, but not in any of 43 low-grade glioma samples tested. The fusion, caused by tandem duplication on 4p16.3, led to the loss of the 3'-UTR of FGFR3, blocking gene regulation of miR-99a and enhancing expression of the fusion gene. The fusion gene was mutually exclusive with EGFR, PDGFR, or MET amplification. Using cultured glioblastoma cells and a mouse xenograft model, we found that fusion protein expression promoted cell proliferation and tumor progression, while WT FGFR3 protein was not tumorigenic, even under forced overexpression. These results demonstrated that the FGFR3-TACC3 gene fusion is expressed in human cancer and generates an oncogenic protein that promotes tumorigenesis in glioblastoma.
Authors:
Brittany C Parker; Matti J Annala; David E Cogdell; Kirsi J Granberg; Yan Sun; Ping Ji; Xia Li; Joy Gumin; Hong Zheng; Limei Hu; Olli Yli-Harja; Hannu Haapasalo; Tapio Visakorpi; Xiuping Liu; Chang-Gong Liu; Raymond Sawaya; Gregory N Fuller; Kexin Chen; Frederick F Lang; Matti Nykter; Wei Zhang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-09
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-09-24    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  855-65     Citation Subset:  AIM; IM    
Affiliation:
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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MeSH Terms
Descriptor/Qualifier:
3' Untranslated Regions
Animals
Base Sequence
Brain Neoplasms / genetics*,  metabolism
Chromosomes, Human, Pair 4 / genetics
Gene Expression Regulation, Neoplastic
Gene Fusion*
Glioblastoma / genetics*,  metabolism
Glioma / genetics,  metabolism
Humans
Male
Mice
Mice, Nude
MicroRNAs / genetics*,  metabolism
Microtubule-Associated Proteins / genetics*,  metabolism
Molecular Sequence Data
Oncogene Proteins, Fusion / genetics,  metabolism
RNA, Neoplasm / genetics
Receptor, Fibroblast Growth Factor, Type 3 / genetics*,  metabolism
Tandem Repeat Sequences
Transplantation, Heterologous
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA016672/CA/NCI NIH HHS; P30 CA016672/CA/NCI NIH HHS; U24CA143835/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/3' Untranslated Regions; 0/MIRN99 microRNA, human; 0/MicroRNAs; 0/Microtubule-Associated Proteins; 0/Oncogene Proteins, Fusion; 0/RNA, Neoplasm; 0/TACC3 protein, human; EC 2.7.10.1/FGFR3 protein, human; EC 2.7.10.1/Receptor, Fibroblast Growth Factor, Type 3
Comments/Corrections
Comment In:
J Clin Invest. 2013 Feb 1;123(2):548-51   [PMID:  23298839 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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